Retinal ischemia occurs when the oxygen and glucose supply to the retina is interrupted. The pathophysiology involves changes in cellular biochemistry or energy level, blood flow and gene expression. Previous work related to this project has shown, among other things, a complex involvement of adenosine in the pathophysiology of retinal ischemia-reperfusion injury. In addition the phenomenon of retinal pre-conditioning was demonstrated, whereby a brief period of non-damaging ischemia 24 or 72 hours before prolonged ischemia completely preserved retinal function and morphology. This process appears to require protein synthesis and preliminary data shows that adenosine may be a key factor in the initiation of preconditioning. Proposed experiments will use biochemical, morphological and functional measurements to examine mechanisms and effects of adenosine on retinal ischemia. The long-term goal is to characterize endogenous protective mechanisms against ischemic injury in the retina and to use this information to develop clinically relevant treatment strategies of retinal ischemic diseases. Three specific aims are proposed: (1) to characterize basic mechanisms and limitations of preconditioning and the role of adenosine as an initiator of preconditioning; (2) to examine the effect of altered adenosine metabolism in retinal function and structure during severe ischemia; and (3) to test mechanisms of adenosine receptor-mediated protection against retinal ischemic injury. These studies are relevant to acute disease states such as retinal arterial occlusion, or to chronic diseases that also result in ischemia, such as diabetic retinopathy.